Method for treating coumarin-induced hemorrhage

ABSTRACT

Use of factor XIII for treating coumarin-induced hemorrhage or bleeding. The coumarin may be warfarin or dicoumarol. A patient having coumarin-induced bleeding is treated with factor XIII alone or in conjunction with vitamin K.

BACKGROUND OF THE INVENTION

[0001] Vitamin K controls the formation of prothrombin, factor VII,factor IX, and factor X by acting as a substrate for the enzymeγ-glutamyl carboxylase. This enzyme catalyzes the addition of carbondioxide to the γ-carbon of protein-bound glutamic acid in the glaregions of the coagulation factors.

[0002] Coumarin anticoagulants, which include warfarin and dicumarol(dicoumarol), prevent the reduction of vitamin K epoxides in the livermicrosomes and induce a state of vitamin K deficiency. A side effect ofsuch anticoagulants is hemorrhage. If hemorrhage does occur, there is aneed for a substance to inhibit the coumarin anticoagulant-inducedbleeding.

DESCRIPTION OF THE INVENTION

[0003] The present invention fills this need by administering factorXIII to patients afflicted with bleeding due to a coumarinanticoagulant-induced vitamin K deficiency. Factor XIII can beadministered alone or in conjunction with cryoprecipitate or freshfrozen plasma, generally two units or plasma. Vitamin K can also beadministered at an initial dose of 5 to 10 mg, generally subcutaneously.The administration of factor XIII can be applied prophylactically or atthe time of a bleeding episode.

[0004] Factor XIII, also known as fibrin-stabilizing factor, circulatesin the plasma at a concentration of 20 μg/ml. The protein exists inplasma as a tetramer comprised of two A subunits and two B subunits.Each subunit has a molecular weight of 83,000 Da, and the completeprotein has a molecular weight of approximately 330,000 Da. Factor XIIIcatalyzes the cross-linkage between the γ-glutamyl and ε-lysyl groups ofdifferent fibrin strands. The catalytic activity of factor XIII residesin the A subunits. The B subunits act as carriers for the A subunits inplasma factor XIII. Recombinant factor XIII can be produced according tothe process described in European Patent No. 0 268 772 B1. The level offactor XIII in the plasma can be increased by administering a factorXIII concentrate, derived from human placenta or plasma, calledFIBROGAMMIN® (Aventis Corp.) or by administration of recombinant factorXIII. When recombinant factor XIII is used, only the ‘A₂’homodimer isgenerally administered without the ‘B₂’ subunit.

[0005] Administration of factor XIII to a subject is generally doneintravenously. When administering therapeutic proteins by injection, theadministration may be by continuous infusion or by single or multipleboluses. A pharmaceutical composition comprising factor XIII can beformulated according to known methods to prepare pharmaceutically usefulcompositions, whereby the therapeutic proteins are combined in a mixturewith a pharmaceutically acceptable carrier. A composition is said to bea “pharmaceutically acceptable carrier” if its administration can betolerated by a recipient patient. A suitable pharmaceutical compositionof factor XIII will contain 1 mM EDTA, 10 mM Glycine, 2% sucrose inwater. An alternative formulation will be a factor XIII compositioncontaining 20 mM histidine, 3% wt/volume sucrose, 2 mM glycine and 0.01%wt/vol. polysorbate, pH 8.

[0006] Other suitable carriers are well known to those in the art. See,for example, Gennaro (ed.), Remington's Pharmaceutical Sciences, 19thEdition (Mack Publishing Company 1995).

[0007] The levels of factor XIII in an individual can be determined byassays well known in the art such as the BERICHROM® F XIII assay (DadeBehring Marburgh GmbH, Marburg, Germany). The normal adult has anaverage of about 45 ml of plasma per kg of body weight. Each liter ofblood has 1000 units (U) of factor XIII. The amount of factor XIIIadministered should be enough to bring an individual's level of factorXIII in the plasma to at least 100% of normal plasma or preferably 1-5%above normal. A dose of 0.45 U/kg would raise the level of factor XIIIby about 1% compared to normal. One unit of factor XIII is about 10 μgof recombinant factor XIII, which contains only the dimerized A subunit.Thus, to raise the level of factor XIII by 1%, one would administerabout 4.5 μg of the A2 subunit per kilogram weight of the individual. Soto raise the level 30% of normal, one would administer 13.5 U/kg. For a75 kg individual this would be about 1,012.5 U. Some patients may haveconsumptive coagulopathies that involve factor XIII losses. In suchcases, a higher dosing (e.g., 1-2 U/kg-%) or multiple dosing of factorXIII (e.g., 1-2 U/kg-%-day) may be required.

What is claimed is:
 1. A method for stopping coumarinanticoagulant-induced bleeding or hemorrhage in an individual comprisingadministering to said individual a therapeutically effective amount offactor XIII.
 2. The method of claim 1 wherein the anticoagulant iswarfarin or dicoumarol.
 3. The method of claim 1 wherein the factor XIIIis administered in conjunction with vitamin K.
 4. The method of claim 1wherein cryoprecipitate or fresh frozen plasma is administered inconjunction with the factor XIII.
 5. The method of claim 1 wherein thefactor XIII is recombinant human factor XIII.
 6. The use of factor XIIIfor the production of a medicament for the treatment of coumarin-inducedbleeding or hemorrhaging in an individual.
 7. The use of factor XIII inconjunction with vitamin K for the production of a medicament for thetreatment of coumarin-induced bleeding or hemorrhaging.
 8. The use offactor XIII in conjunction with a plasma-derived cryoprecipitate orfresh frozen plasma for the production of a medicament for the treatmentof coumarin-induced bleeding or hemorrhaging
 9. The use of factor XIIIas recited in claims 6, 7 or 8 wherein the coumarin-induced bleeding iscaused by warfarin or dicoumarol.
 10. The use of factor XIII as recitedin claims 6, 7, 8, or 9 wherein the factor XIII is recombinant factorXIII.